A number of imidazopyrazine compounds are under investigation for inhibiting Spleen Tyrosine Kinase (Syk) activity. Syk is a non-receptor tyrosine kinase that plays critical roles in immunoreceptor- and integrin-mediated signaling in a variety of cell types, including B-cells, macrophages, monocytes, mast cells, eosinophils, basophils, neutrophils, dendritic cells, T-cells, natural killer cells, platelets, and osteoclasts.
Syk has been reported to play an important role in signaling through the B-cell receptor, known to be an important survival signal in B-cells. As such, inhibition of Syk activity may be useful for treating certain types of hematologic malignancies. Examples of such hematologic malignancies include cancer, such as B-cell lymphoma and leukemia. Furthermore, there are reports of Syk expression in certain solid cancer (tumor) cell lines. Examples of such solid cancer tumors include pancreatic cancer, lung cancer, colon and colo-rectal cancer, ovarian cancer and hepatocellular cancer. Additionally, the inhibition of Syk activity is believed to be useful for treating of other diseases and conditions, including inflammatory diseases (e.g., rheumatoid arthritis), allergic disorders and autoimmune diseases.
One such compound that has been found to inhibit Syk activity is represented by formula I:
or a pharmaceutically acceptable salt thereof. The compound of formula has the chemical name 6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine. This compound and its synthesis have been described in U.S. Pat. Nos. 8,450,321 and 8,455,493, which are hereby incorporated by reference in their entirety and specifically with respect to the method of making this compound. See e.g., U.S. Pat. No. 8,450,321, Examples 1 and 2.
Vinca-alkaloids are a subset of drugs derived from the Madagascar periwinkle plant that were discovered in the 1950's, and have a variety of uses from treating diabetes, high blood pressure, and cancer. There are approximately 10 (ten) vinca-alkaloids either currently in use or in development for these indications, including the four major vinca-alkaloids in clinical oncology use: vinblastine, vinorelbine, vincristine, and vindesine. Each of these major vinca-alkaloids has been reported to cause serious side effects, most notably neuropathy. One of the more commonly known vinca-alkaloids is vincristine (VCR), also known as leurocristine and marketed as Oncovin. As with other vinca-alkaloids, vincristine is useful in cancer chemotherapy as a mitotic inhibitor and is commonly used in the standard of care regimen CHOP (Cyclophosphamide, Hydroxydaunortibicin (also known as doxyrubicin), Oncovin (vincristine) and Prednisone) for non-Hodgkin's disease or R-CHOP (CHOP in combination with Rituxan® (also known as rituximab) for B-cell lymphomas. However, vincristine also shares several serious side effects with the other vinca-alkaloids, the most serious of which is chemotherapy-induced peripheral neuropathy, a progressive, enduring, often irreversible neuropathy. This neuropathy can be so severe as to result in the reduction or even cessation of use of vincristine.
What is desired are methods for treating diseases responsive to the inhibition of Syk in subjects in need of such treatment, including in subjects who may be considered at risk for the disease, are refractory to standard treatments, and/or are in relapse after standard treatments, wherein a treatment regimen of a Syk inhibitor alone does not result in inhibition of cell activity, especially for subjects who may be sensitive to neuropathy secondary to standard dosing levels of vincristine or vinca-alkaloid containing treatment regimens.